Substituted glycerol ethers



United States Patent- O SUBSTITUTED GLYCEROL ETHERS, Harry Leo Dickiscn and Lee C. Cheney," Fayetteville, N. Y., assignors to Bristol Laboratories Inc., Syracuse, N. Y., a corporation of New York No Drawing. Application August 2, 1952, i Serial No. 302,424

6 Claims. or. 260-2934) This invention relates to a class of organic compounds of therapeutic value and to methods 'for the preparation thereof. More particularly. this invention relatesto a series of basically substituted ethers of glycerol.

The new compounds of the present invention are the free bases, the acidaddition salts and the quaternary salts of the bases which may be represented by the following general formula:

wherein R1 and R2 represent members selected from the I 1 group consisting of alkyl, aralkyl, aryl, cycloalkyl, nitrosubstituted' aryl, halogen-substituted aryl, alkyl-substituted aryl, and alkoxy-substituted aryl; X, Y, and Z rep-,

resent members selected from the group consisting of O, S and S02; ALK represents straight and branched chain bivalent alkylene radicals containing from one to six carbon atoms inclusive; and B represents a member selected from the group consisting of di(lower)a1kylamino, piperidino, morpholino, pyrrolidino, (lower)alkylpyrrolidino, N-alkyl-piper azino, and pipecolino.

- The compounds of this invention are useful local anesthetic agents which are of value in veterinary and clinical medicine. The compounds .of the present invention may be prepared in general via conversion of the particular 1,3-di- (substituted)-2-propanol into the corresponding'alkali salt by employing a suitable inert solvent, such as toluene, for the substituted 2-propanol and heating and stirring this solution with somewhat less than the stoichiometrical amount of an alkali metal, an alkali metal amide or an alkali metal hydride until the formation of the corresponding alkali salt is substantially complete.- The appropriate tertiary-aminoalkyl halide is then added to the reaction flask and heating is continued until the ether is formed.

The product can be purified by distillation under reduced V pressure or by recrystallization of a suitable salt, such as the hydrochloride or dihydrogen citrate from a favorable solvent.

.It is apparent to' one skilled in the art that other methods of synthesis can be devised. For example, a 1,3- disubstituted-Z-propyl halide can be caused to react with 'an alkali metalsalt of the appropriate alcohol. Alternatively, the basic ethers can be prepared by causing an alkali salt of 1,3-disubstituted-2-propanol to react with an equivalent quantity of an alkylene dihalide; the halogenated alkyl ether thus formed can then be caused to react with a secondary or tertiary amine to give ,the desired product or with potassium phthal-imide ora primary amine to give the desired product after additional isolation and alkylation. The mercapto compounds are oxidized to sulfones in the usual manner, as with potassium permanganate. I Y The following examples will serve to illustrate the in vention without limiting it thereto.

Patented Mar. 13, 1956 2 EXAMPLE I p i,3-bis(p-chlor0phenoxy)-2-pr0pan0l A mixture of 282.5 g. (2.2 moles) of p-chlorophenol and 48 g. (1.2 moles) of flake sodium hydroxide in 200 ml. of dioxane is heated for thirty minutes on the'steam bath with mechanical stirring. With continued heating and stirring, 92.5 g. (1 mole) of epichlorohydrin is added over a forty-five minute period. The mixture is stirred and heated for 5 /2 hours and poured into 800 cc. of water. The precipitated oil crystallizes on cooling. It is collected by filtration, washed with water, and recrystallized from isopropyl alcohol. The product, M. P. 91-92 C., is obtained.

By the method of Example I, employing 188.4 g. (1.54 moles) of 3,5-xylenol, 33.6 g. (0.84 mole) of flake sodium hydroxide, 64.8 g. (0.7 mole) of epichlorohydrin and 200 ml. of dioxane, the aforementioned product is prepared. Subsequent recrystallizations from isopropyl alcohol, cyclohexane-Skellysolve A, and Skellysolve B, yield the product; M. P. 6869 C.

Analysis.-Calculated for C19H24O3:

Calculated Found o. 75.9 76.1 H I 8.04 7.83

EXAMPLE III This compound is prepared by the method of Example I, utilizing 213.0 g. (1.54 moles) of p-ethoxyphenol, 33.6 g. (0.84 mole) of flake sodium hydroxide, 64.8 g. (0.70 mole) of epichlorohydrin and 200 ml. of dioxane; The product is obtained after one recrystallization from iso propyl alcohol; M. P. 9596.5 C.

Analysis.-Calculated for C19H24O5:

Calculated Found C 68. 6 6B. 8 H 7. 26 V 7. 09

3 4 EXAMPLE IV EXAMPLE VII 1,3-bis(4-chlore-3,5-xylyl0xy)-2-pr0pan0l 1,3-bis(phenylmercapto)-2-propan0l CH: CH!

5 S-CHr-CHCHr-S c1 -o-oH-OH-o11 o -c1 I I 0H 0H J H3 A mixture of 61.7 g. (0.56 mole) of thiophenol and By the procedure of Example I, using 172.3 g. (1.1 12.8 g. (0.32 mole) of flake sodium hydroxide in 100 moles) of 4-chloro-3,5-xylenol, 24.0 g. (0.6 mole) of ml. of dioxane is stirred and heated for one hour on the flake sodium hydroxide, 46.3 g. (0.5 mole) epichlorobath and mole) of epichlol'ohydrin hydrin, and 200 ml. of dioxane, the aforementioned com- 1S aqded thehomogeneous miXtllre, with Continufid pound is prepared. Recrystallizations, with use of charheatlflg and Stimng, zo-millute p The coal, f skellysolve and sk l l i iture 1s heated for five hours and poured into Water. The fied product; M. P. 89-90 C. precipitated oil is extracted into chloroform and the Analysis' ca]cu1ated f C19H22C12O3; combined extracts are washed with water, saturated sodium chloride solution, and filtered through anhydrous C1 1 d F d magnesium sulfate. Distillation yields a small forerun a cu am of diphenyl disulfide and the product as a viscous yellow 0 H 61.9 M8 20 oil of B. P. 192 C./1 mm. to 225 C./3.5 mm. H111:I:I:I:IIII:IIIIIIIIIIIII II.-IIII 6.00 5.00 Analysis.Calculated for C15H1s0S2:

XA V Calculated Found 1,3-bis(2,4-dichl0r0phenoxy)-2-pr0pan0l C 05.1 65.2

01 Cl oi-o om-on-on,-o oi EXAMPLE VIII 5 1,3-bis(0-methylphenylmercapto)-2-propanol This compound is prepared by the procedure of Ex- CH; CH! ample I, using 150.0 g. (0.92 mole) of 2,4-dichlorophenol, 1 20.0 g. (0.50 mole) of flake sodium hydroxide, 39.0 g. CH CH (0.42 mole) of epichlorohydrin, and 100 ml. of dioxane. P The crude product is obtained. Recrystallizations with CH use of charcoal, from isopropyl alcohol acetone, and This com i a pound is prepared by the procedure of Exethyl alcohol give product of M. P. 128.5-129 C. ample VII, employing 496 (038 mole) of Analyslscalculated for C15H12c103' cresol, 11.2 g. (0.28 mole) of flake sodium hydroxide,

65 ml. of dioxane and 16.7 g. (0.18 mole) of epichloro- Calculated Found hydrin. The product is obtained as a yellow oil boiling at 208218 C./less than 1 mm. o 47.1 47.3 Analysis.-Calculated for C17H20OS2: H a. 16 3.52

Calculated Found- EXAMPLEVI G 07.0 07.2 1,3-bis(2,4,5-trichlorophenoxy)-2-pr0panol EXAMPLE IX D EZ Q 1-(o-methylphenylmercapto)-3-phenoxy-2 propanol 01 1 OH: By the utilization of 83.0 g. 0.42 mole) of 2,4,5-trichlorophenol, 8.8 g. (0.22 mole) of flake sodium hydroxide, 50 ml. of dioxane, and 19.5 g. (0.20 mole) of 0H epichlorohydrin, the aforementioned compound is prepared by the procedure of Example I. The product does 0f y y P y ether 15 added not crystallize when the reaction mixture is poured into Over 3 45111111136 P to a Solutlon 8- (9- water and is extracted into chloroform. The combined m of O-thwcresol m 110 of dloxanc h h 1s chloroform extracts are washed with 10% sodium hy surfed f heated on Steam. bath- After 19 9 droxide, water, and saturated sodium chloride solution. heatlng, Cooled mtxmre 1S eXtfaQted three tlmqs Drying over anhydrous magnesium sulfate and removal Wlth 5% Sodlllm y f Washed W1th Water nt l of the solvent by distillation yields 63.0 g. of dark, Washed 01166 l t rat d S dium chloride gummy solid. Recrystallizations from acetone, ethyl al- 1 0 andfilteled through anhydrous f cohol, and isopropyl alcohol give a white product; M. P. nlstlllatlon Ylelds the Product as a Yellow 011 of P. 124 5 127 C l84-19l C. at less than 1 mm.

Analysis-Calculated for C15H10Cls03: A"alySiS-Calm11at6d for ie 18 23 Calculated Found Calculated Found '0 39.9 40.0 70.0 70.2 rr 2.23 2.30 H 6.61 6.75

EXAMPLE x A mixture of 37.4 g. (0.34 mole) of 'thiophenol and 14.4 g. (0.36 mole) of flake sodium hydroxide in 100 m1. of dioxane is stirred and heated on the steam bath for one hour. To the resultant mixture is added 66.5 g. (0.33 mole) of 1-chloro-3-(o-t0loxy)-2-propanol (prepared by the method of Boyd and Marle, J. C. S. 97, 1788) over a half-hour period. After five hours of 'heating, the mixture is poured into water. The precipitated oil is collected by three extractions with chloroform, the combined extracts are washed with Water and saturated sodium chloride solution and filtered through anhydrous magnesium sulfate. Distillation yields the product, boiling from 183 0. /1 mm. to 210 C./3.5 mm., the majority beingcollected at 205-210 C./ 3.5 mm.

Analysis.-Calculated for CIGHISOZSI Calculated Found EXAMPLE XI 1-ethylmercapt0-3-(0-t0loxy)-2-pr0pan0l A mixture of 33.0 g. (0.53 mole) of ethyl'mercaptan and 14 g. (0.35 mole) of flake sodium hydroxide in 75 ml. of dioxane is stirred and heated at C. for 50 I minutes. 64.5 g. (0.32 mole) of 1-chloro-3-(o-toloxy)- 2-propanol (prepared by the method of Boyd and Marle, J. C. S. 97, 1788) is added during 15 minutes at room temperature and the mixture 'is heated and stirred for six hours on the steam bath. It is poured into water, and the oily product is extracted into ether. The combined ethereal extracts are washed with 10% sodium hydroxide, water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate and distilled. The product is obtained as a light yellow oil, B. P. 141.5 C./less than 1 mm. to 149 C./ 1.5 mm.

Analysis.-Calculated for C1aH1s02S:

Calculated Found N,N-dimethyl-2-[(1,3-diphen0xy)-2-pr0p0xy]-ethylamine TMQ hydroxide and extraction 100 ml. of toluene in four portions. The reaction mixture is refluxed for 8 hours, cooled, and -enough"water is added to dissolve the precipitated sodium chloride' The toluene layer is separated, washed several times with water, and extracted with 3 M hydrochloric acid. The combined acid extracts are neutralized with 50% sodium hydroxide and extracted with ether. Drying of the combined ether extracts and distillation yields the product, B. P. 152160 C./less than 1 mm. 30.2 g. of this oil is dissolved in anhydrous ether and the hydrochloride is prepared by saturation of the solution with dry hydrogen chloride. One recrystallization from methyl iso-butyl ketone gives a white product, M. P. 131132 C.

Analysis: For C19H26C1N032 Calculated Found A solution of 7.0 g. (0.022 mole) of N,N-.dimethyl[ (1,3-diphenoxy)-2-propoxy]ethylamine and 4 ml. (7.8 g.) (0.05 mole) of ethyl iodide in 40 ml. of isopropyl alcohol is allowed to stand at room temperature for one day. The solvent and excess ethyl iodide are removed by distillation, and crystallization of the residual oil is induced by addition of anhydrous ether and scratching. Crystallization from absolute ethyl alcohol-ethyl acetate gives white needles; M. P. 7576.5 C.

Analysis-Calculated for C21H30INO3:

Calculated EXAMPLE XIII N,N-diethyl 2 [(1,3-diphen0xy)-2-pr0poxy]ethylamine .E fQ

Calculated The dihydrogen citrate is prepared by addition of a saturated aqueous solution of citric acid to a toluene solution of the base. After successive recrystallizations from water and isopropyl alcohol, it melts at 1131l4.5 C

Analysis.Calculated for Cz'zHs'lNOio:

Calculated B. An alternative procedure on-the preparation of N,N-diethyl-2- 1,3-diphenoxy)-2-propoxy] ethylamineis as-follows: j -j A mixture of 24.4 g. (0.10 mole) of 1,3-bis(phen oxy)- 2-propanol, 2.6 g. (0.11 mole) of lithium amide and 75 ml. of toluene is slowly raised to reflux and refluxed for four hours. A toluene solution of beta-diethylaminoethyl chloride, prepared from 19.0 g. (0.11 mole) of the a corresponding hydrochloride as outlined in Example XII, is added over a 30-minute period and the mixture is refluxed for 17 hours. Enough water is added to destroy excess lithium amide and dissolve all inorganic material and the toluene layer is washed several times with water. Extraction of the toluene with dilute hydrochloric acid and neutralization of the extracts with 50% sodium hydroxide yields the crude basic ether. This is converted to the dihydrogen citrate by adding it to a saturated acetone solution of the citric acid. Subsequent recrystallizations from water and isopropyl alcohol give a white product.

Treatment of the free base with n-propyl iodide according to the method of Example XII, produces the quaternary n-propiodide.

EXAMPLE XIV N -2- (1 ,3-diphenxy -2-prop0xy] ethylpiperidine l TH-O-CHr-CH:N H

Calculated Found A solution of 5.8 g. (0.016 mole) of 2-[(1,3-diphenoxy)-2-propoxy] ethylpiperidine and 5.7 g. (0.040 mole) of methyl iodide in ml. of isopropyl alcohol is allowed to stand .two days. After removal of the solvent and excess methyl iodide by distillation, crystallization of the residual oil is induced by addition of anhydrous ether and scratching. Two ,recrystallizations from absolute alcoholether yield the product; M. P. 78-80 C.

Analysis-Calculated for C23H32INO32 Calculated Found EXAMPLE XV N ,N -dieth yl-2- (1 ,3 -di-p-ch lorophenoxy -2 -pr0p0xy] ethylamine 0 LHPO a This compound is prepared by the method of Example XIII-B, using 62.6 g. (0.20 mole) of l,3-bis(-p-chlorophenoxy)-2-propanol, 5.5 g. (0.23 mole) of lithium amide,

41.3 g. (0.24 mole) of beta-diethylaminoethyl .chloride hydrochloride, 350 ml. of toluene and 42.3 g. (0.22 mole) of citric acid. However, the method of isolation differs as follows: After a final reflux of 19 hours, the reaction mixture is cooled and an aqueous solution of 42.3 g. (0.22 mole) of citric acid is added. The mixture is heated to reflux for a few minutes and the two lower layers are separated. Crystallization of the middle layer is induced by cooling and scratching, and the product is collected by filtration. Subsequent recrystallizations from water, acctonc, and ethyl alcohol give a white product; M. P. 122- 123 C.

Analysis.Calculated for C27H35CI2NO10:

Treatment of the free base with methyl sulfate produces the quaternary methosulfate salt.

EXAMPLE XVI N ,N-diethyl-Z- (1 ,3-diphenylmercapto) -2-prop0xy] ethylamine A solution of 39.5 g. (0.143 mole) of l,3-bis(phenylmercapto)-2-propanol in ml. of toluene is added during 45 minutes to a stirred suspension of 2.8 g. (0.122 mole) of molten sodium in ml. of toluene. After two hours of reflux under nitrogen, a solution of beta-diethylaminoethyl chloride in 100 ml. of toluene prepared from 25 g. (0.145 mole) of the hydrochloride by the method of Example Xll is added over a ten-minute period and the reaction mixture is refluxed for 20 hours. The mixture is cooled, enough water is added to dissolve all inorganic products, the toluene layer is washed twice with water and extracted three times with 25-ml. portions of 6 N hydrochloric acid. The combined acid extracts are neutralized with 50% sodium hydroxide, extracted with ether and the combined ether extracts are dried over anhydrous potassium carbonate and stripped, yielding a reddish oil.

38.6 grams of this crude product is dissolved in 75 ml. of acetone and treated with a solution of 20.6 g. 0.11 mole) of anhydrous citric acid in 75 ml. of acetone. The crude dihydrogen citrate is recrystallized once each from ethyl alcohol and acetone to yield a white product of M. P. 91"-.-92.5 C.

Analaysis.-Calculated for C2'1H37NOaS2 /21-120:

Treatment of the free base with methyl p-toluenesulfonate produces the quaternary metho-p-toluenesulfonate.

EXAMPLE XVII N,N-dimethyl-2-[ (1 -phenylmercapt0-3'0-t0l0xy) -2- propoxy] ethylamine LEAF 9 Following themethod of Example XVI, substituting 46.8 g. (0.17 mole) of l-phenylmercapto)-3-(o-toloxy)- 2-propanol, 3.5 g. (0.15 mole) of sodium and 28.8 g. (0.20 mole) of beta-dimethylaminoethyl chloride hydrochloride, this product was isolated as a crude. Distillation yielded a heavy, yellow oil, boiling at 208 C./1 mm. to 217 C./1.5 mm.

Analysis-Calculated for CzoHzvNOzS:

Calculated Found Treatment of the free base with sulfuric acid and with n-butylbromide produces the sulfate and the n-butobromid'e respectively.

EXAMPLE XVIII N, N-diethyl-2-( (1,3-di-p-nitrophen0xy -2-pr0poxy ethylamine (fHr-O-Q-NO z l..-o m.

By employing the procedure of Example XIII-B, using 6.7 g. (0.02 mole) of l,3-bis(p-nitrophenoxy) -2-propanol, 0.9 g. (0.04 mole) of lithium amide, and 4.3 g. (0.025 mole) of beta-diethylaminocthyl chloride hydrochloride, this compound is isolated, Without distillation, in a crude yield as a yellow, crystalline solid. Two recrystallizations from ethyl alcohol and one from ethyl acetate give a product of M. P.98 -100 C.

Analysis-Calculation for: C21H27N3O7:

Using the method of Example XVI, but substituting 40.6 g. (0.20 mole) of 1-butoxy-3-phenoxy-2-propanol [Hine et al., J. Pharmacol. and Exptl. Therapeutics, 97,

Pt. I, 414-19 (1949)], 3.7 g. (0.16 mole) of sodium and 34.4 g. (0.20 mole) of beta-diethylaminoethyl chloride hydrochloride, the above product is prepared as a'crude. Distillation gives a colorless oil; B. P.-152 C./ 1 mm. to 162 C./l mm.

Analysis.-Calculated for C19H33NO3:

Calculated Found Treatment of the free base with hydrobromic acid and with n-hexyl iodide produces the hydrobromidexand .the n-hexiodide respectively.

10 EXAMPLE XX N,N-d iet hyl-2-[(1 o-methylphenyImercapt0-3-phenoxy)- Z-propoxy] ethylamine IMQ H-O-CHz-C Hr-N(C di a By employing the method of Example XVI, substituting 20.2 g. (0.073 'mole) of 1-(o-methylphenylmercapto)-3- phenoxy-Z-propanol in 75 ml. of toluene, 1.6 g. (0.070 mole)'of sodium in 50 m1. of toluene and 14.6 g. (0.085 mole) of beta-diethylaminoethyl chloride hydrochloride, the above product is prepared and has B. P.--'l 86-89/ 1 mm.

Analysis-Calculated for C22Hs1NO2S:

Calculated Found The dihydrogen citrate is prepared in acetone, one

recrystallization from isopropyl alcohol yielding a white product; M. P.-ll2l13.5 C. v

Analysis-Calculated for C2aH39NO9S:

Calculated Found Treatmentof the free base with ethyl sulfate produces the ethosulfate.

EXAMPLE XXI N ,N -dimethyl-2-[ (1,3-di-o-methylphenylmercapto) -2- propoxy] ethylamine LEWQ Followingthe procedure of Example XVI, using 35.6 g. (0.116 mole) of 1,3 bis(o methylphenylmercapto)-2- propanol in 75 ml. of toluene, 2.3 g. (0.100 mole) of sodium in ml. of toluene and 17.3 g. (0.120 mole) of beta-dimethylaminoethyl chloride hydrochloride, this compound is obtained as a viscous yellow oil; B. P.- 193-199 C./ l mm.

Analysis.--Calculated for C21H29NOS2:

Calculated Found C 67. 1 66.6 and 66.4. H. 7. 80 7.72 and 7.56.

The hydrochloride is prepared in ether and recrystallized twice from ethyl acetate; M. P.103l05 C.

Analysis- -Calculated for C21H30C1NOS2:

Calculated Found The n-hexochloride is prepared by reacting the free base iwithn-hexyl chloride under'elevate'd conditions of temperature and'pressure.

.1 1 EXAMPLE xxn N,N-diethyl-Z-l(.1-ethylmencapto-3-o-toloxy) 2- propoxy] ethylamine Calculated Found The dihydrogen citrate is prepared in acetone and recrystallized from methyl isobutyl ketone; 'M. P.--89 90 C.

Analysis-Calculated for C24HsnNO9S:

Calculated Found C 55.7 HQ. 7.5

a The methobromide is prepared by reacting .the free base with methyl bromide.

EXAMPLE XXIII Ethyl (I ,3-diphen0xy) -2-pr0p0xy acetate saturated sodium chloride and dried over anhydrous sodium sulfate. Distillation yields a viscous oil boiling at 210214 C./1.5 mm.

Analysis-Calculated for Ciel-12205:

Calculated Found EXAMPLE XXIV 2-( (1,3-diphenoxy) -2-pr0poxymethyl) imidazoline CHz-O-CsHs N-CH:

("JH O C H:C C Hr-O-C 0H5 li H A mixture of 33.0 g. (0.1 mole) of .eI ltK( id-diphenoxy)-2-propoxy)acetate and 130.10g. (0.5 mole) of anhydrous ethylenediamine is heated for 89 hours on the 12 steam bath with protection from moisture. Water, alcohol, and excess ethylenediarnine are removed by dis.- tillation, and the residual heavy oil is distilled in vacuo, yielding a red-brown oil of B. P. 238-24l C./2 mm. The hydrochloride is prepared by saturation of an ether solution of the oil with dry hydrogen chloride. Two re crystallizations from isopropyl alcohol give a white product; M. P.-168168.5 C.

Analysis.Calculation for C19H23C1N2O3:

Calculated Found Additional examples within the scope of this inv ntion which may be made by the methods disclosed above include the following: 1. N,N-di-n-butyl-2-( (1-phenoxy-3-para-chlorophenoxy)- Z-propoxy isopropylamine 2. N,N di isopropyl 2-((1-p-tolyloxy-3-ortho-chlorophenoxy) -2-propoxy) -2-methyl-isopropylamine 3. N,N di isohexyl 4((1 -methoxy-3-para-methoxyphenoxy) -Z-propoxy)-n-butylamine 4. N,N di n amyl-3((1-benzyloxy-3-cyclohexyloxy)- 2-propoxy) -n-propylamine 5. N 2((1 cyclopentyloxy 3 n-propoxy)-2-propoxy) methyl-piperidine 6. N 3((1 n butylmercapto 3 methylmercapto.) 2-

propoxy) -n-propylpyrrolidine 7. N methyl N 4-((1-n-amylmercapto-3-n-propoxy)- 2-propylmercapto) -n-butylpiperazine 8. N 2-((1,3-di-ethylmercapto)-2-propylmercapto)ethyl- 'y-pipecoline 9. 2 methyl N 2((1 isobutylmercapto 3-ethoxy)-2- propyl-mercapto) -ethyl-pyrrolidine 10. N 2 ((1-benzyloxy-3-cyclohexyloxy)-2-propoxy)- isopropyl-a-pipecoline 11. N 3 ((l orthomethoxyphenoxy-3-m-tolyloxy)-2- propoxy) -n-propylmorpholine 12. N ethyl N 6((1 cycloheptyloxy 3 ortho-nitrophenoxy) -2-propylmercapto -n-hexylpip erazine 13. Phenyl 3 phenoxy 2 diethylaminoethoxy-n-propyl sulfone 14. n-Butyl 3-phenylmercapto-2-dimethylaminoethoxy-npropyl sulfone 15. o-Tolyl 3 para chlorophenoxy-2-(di-n-propylarninoethylmercapto) -n-propyl sulfone 16. Dimethylaminoethyl 1,3-diphenoxy-2-propyl sulfone The invention also contemplates the non-toxic organic and inorganic acid addition salts of the compounds having the general formula above such as will be readily formed with, for example, organic and inorganic acids such as hydrochloric, sulfuric, sulfamic, tartaric, hydrobromic, hydriodic, glycolic, citric, maleic, phosphate, succinic, acetic, benzoic, cinnamic, mandelic, malic, ascorbic, and the like. The method of preparation of these salts is made apparent in the examples above.

This invention also contemplates the quaternary salts ofthe free bases of the general formula above, which may be prepared as made apparent in the examples above by treatment of the free bases with quaternary salt-forming substances. These quaternary salt-forming substances include methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, nvpropyl chloride, n-propyl bromide, n-propyl iodide, isopropyl bromide, n-butyl chloride, n-butyl bromide, isobutyl .bromide, sec.-buty1 bromide, n-amyl bromide, n-hexyl chloride, benzylchloride, benzyl bromide, methyl sulfate, ethyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, .etc. which will react directly with any free base .of the general formula above to give respectively the methochloride, methobromide, methiodide, ethochloride, ethobromide, ethiodide, n-propochloride, n-propobromidc,

ii-propiodide, isopropobromide, n-butochloride, n-butobromide, isobutobromide, sec.-butobromide, n-amobromide, n-hexochloride, benzochloride, benzobromide, methosulfate, ethosulfate, methobenzenesulfonate, methop-toluenesulfonate, etc.

In general, the salts are soluble in water and constitute a preferred form of the invention. The organic bases, on the other hand, are generally water-insoluble, but soluble in simple organic solvents such as alcohols, ethers, hydrocarbons, and lower ketones.

We claim:

1. A compound selected from the group consisting of a free base having the structure wherein R1 represents a member selected from the group consisting of (lower)alkyl, phenyl, chlorophenyl, tolyl, and nitrophenyl and R2 represents a member selected from the group consisting of phenyl, chlorophenyl, tolyl and nitrophenyl; X, Y and Z represent members selected from the group consisting of oxygen and sulfur, at least one being oxygen; B represents a member selected from the group consisting of di(lower)a1kylamino, piperidino, morpholino, pyrrolidino, (lower) alkylpyrrolidino, N"- alkylpiperazino and pipecolino; and the non-toxic acid addition salts and the non-toxic quaternary salts of said free base,

2. A compound selected from the group consisting of the free base, the non-toxic acid addition salts and the non-toxic quaternary salts of N,N-dimethyl-2-((1,3- diphenoxy) -2-propoxy) ethylamine.

3. A compound selected from the group consisting of the free base, the non-toxic acid addition salts and the non-toxic quaternary salts of N,N-diethyl-2-((1,3-diphenoxy) -2-propoxy) ethylamine.

4. A compound selected from the group consisting of the free base, the non-toxic acid addition salts and the non-toXic quaternary salts of N-2-((-1,3-diphenoxy)-2- propoxy) ethylpip eridine.

5. A compound selected from the group consisting of the free base, the non-toxic acid addition salts and the non-toxic quaternary salts of N,N-diethyl-2-((1,3-diphenylmercapto) -2-p rop oxy) ethyl amine.

6. A compound selected from the group consisting of the free base, the non-toxic acid addition salts and the non-toxic quaternary salts of N,N-di-isopropyl-2-((1,3-diphenoxy) -2-propoxy) ethylamine.

References Cited in the file of this patent UNITED STATES PATENTS 2,445,356 Kharasch et al. July 20, 1948 FOREIGN PATENTS 560,568 Great Britain Apr. 11, 1948 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A FREE BASE HAVING THE STRUCTURE 